Rheumatoid Arthritis (RA) is the most frequent form of chronic autoimmune arthritis, affecting 0.5-1% of the adult world population (1). The disease is characterised by joint pain, swelling and stiffness, due to synovitis and irreversible joint destruction, ultimately leading to functional disability. At present, RA is diagnosed based on fulfilment of the classification criteria set by the American College of Rheumatology (ACR) in 1987. If at least 4 out of 7 of these primarily clinical classification criteria are fulfilled, the patient is diagnosed with RA (2). The presence of rheumatoid factor (RF) is the only criterion for diagnosis based on objective laboratory findings. The performance of these classification criteria is however far from optimal, especially for early RA. The disease course of early RA is very heterogeneous and early RA patients often do not fulfil 4 of the 7 criteria (3). Also, to meet the ACR criteria, symptoms must last for 6 weeks or more. This results in a low diagnostic sensitivity for RA, ranging from 62% to 90%, and a pronounced diagnostic delay (3-6). Early treatment of RA is however essential in preventing irreversible joint destruction and improving disease outcome, so that early diagnosis of the disease is of utmost importance (7-9).
To improve diagnostic efficiency, it is currently recommended to incorporate anti-CCP antibody (anti-cyclic-citrullinated-peptides antibody, ACPA) testing in addition to RF testing in the diagnostic work-up, as to maximize sensitivity by combining the two markers (3;10;11). In addition to being an early and specific RA marker, anti-CCP antibodies are predictive for RA development in undifferentiated arthritis patients, and presence of these markers in RA is associated with a worse disease course (11-15). However, according to recently published meta-analyses of studies regarding ACPA and RF testing in RA, the sensitivity of anti-CCP antibodies is only moderate (67-68%) despite a high specificity of 95% (16;17). This would imply that 33% of RA patients is anti-CCP antibody negative (ACPA−). The reported sensitivity for ACPA testing in early disease is even lower (16). Moreover, recent findings indicate a potentially different aetiology and pathogenesis in ACPA negative and ACPA positive RA (18-20). This heterogeneity implies the need for a panel of different markers to achieve an accurate diagnosis for the entire RA patient population.